Successful treatment of a stage IIIC small-cell carcinoma of the ovary hypercalcemic subtype using multi-modality therapeutic approach

Qin, Qian; Ajewole, Veronica B; Sheu, Tiffany G.; Donohue, Rachel; Singh, Monisha

doi:10.3332/ecancer.2018.832

Cited by 12 publications

(14 citation statements)

References 22 publications

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“…In OSCCTH, tumors are generally large in size, with an average diameter of 15 to 16 cm, and a nodular or lobulated appearance with mostly solid or partially cystic sections accompanied by visible hemorrhage and necrosis. [ 1 , 5 ] Histologically, the growth pattern of OSCCTH is solid and trabecular, with typical follicle-like spaces and a sheet-like arrangement of small monomorphic cells, with scanty cytoplasm and round, ovoid, small nuclei containing single, small nucleoli. [ 7 , 10 ] Mitotic figures and necrosis are frequent.…”

Section: Discussionmentioning

confidence: 99%

“…Two-thirds of cases are associated with hypercalcemia, but only 10% of patients have symptoms of hypercalcemia. [ 4 , 5 ] Due to its unclear familial history and vague symptoms, most patients with OSCCHT present late with advanced disease. [ 1 , 5 ] There is little knowledge regarding patients diagnosed with OSCCHT during pregnancy, and only a limited number of case reports can be found in the literature.…”

Section: Introductionmentioning

confidence: 99%

“…[ 4 , 5 ] Due to its unclear familial history and vague symptoms, most patients with OSCCHT present late with advanced disease. [ 1 , 5 ] There is little knowledge regarding patients diagnosed with OSCCHT during pregnancy, and only a limited number of case reports can be found in the literature. [ 6 ] Here, we report the case of a young woman in the third trimester of pregnancy who was diagnosed with OSCCHT, to investigate the clinicopathological characteristics and diagnosis of this disease.…”

Section: Introductionmentioning

confidence: 99%

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Primary ovarian small cell carcinoma of hypercalcemic type in a pregnant woman

Feng

Yang

et al. 2020

Medicine

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Rationale: Ovarian small cell carcinoma of hypercalcemic type (OSCCHT) is a relatively rare and highly fatal gynecological malignancy of unknown histogenesis, affecting mainly girls and young women. OSCCHT occurring during pregnancy is an uncommon event, and preoperative diagnosis of this malignancy is much more difficult in pregnant than non-pregnant women. The aim of this study was to describe a rare case of primary OSCCHT in a pregnant woman and to review the current literature. Patient concerns: Here we present a case of OSCCHT in a 21-year-old patient in the 32nd week of gestation, who had abdominal pain and irregular vaginal bleeding for 5 hours. Because placental abruption, stillbirth, and hemorrhagic shock were suspected, she subsequently underwent diagnostic laparotomy. During the hysterotomy delivery and exploratory laparotomy, we found a dead fetus in the uterus and a large tumor mass arising from her left ovary. Plasma-based detection showed that the patient had a slightly elevated parathyroid hormone (PTH) level and normal serum calcium. After surgery, her serum PTH levels returned to normal. Diagnosis and interventions: The patient was initially treated with surgery. She underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy, as well as the following additional procedures: appendectomy, sigmoidectomy, debulking of extra-ovarian tumor, lymph node dissection, and peritoneal biopsies. The patient, who was in the third trimester of pregnancy, was diagnosed with OSCCHT that was confirmed to be Stage III. She was recommended chemotherapy after surgery, but she declined chemotherapy. Outcomes: Unfortunately, the patient died 5 months after surgery. Lessons: OSCCHT is a very rare and highly aggressive tumor type. The clinical symptoms of this tumor are nonspecific, and pathological examination remains the gold standard for diagnosis. Most patients are diagnosed with advanced stage disease and do not respond to chemotherapy. The prognosis of OSCCHT is generally poor, and no treatment guidelines are available as yet. For pregnant woman, OSCCHT is especially harmful to the mother and may indirectly lead to the death of the fetus.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Primary ovarian small cell carcinoma of hypercalcemic type in a pregnant woman

Feng

Yang

et al. 2020

Medicine

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“…In contrast, OCCC targets women aged 55 years or older and is characterized by mutations in phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) [19,20], and phosphatase and tensin homolog (PTEN), in addition to the ARID1A mutations. Both SCCOHT and OCCC respond poorly to conventional chemotherapy, and to date, there is no consensus on an optimal therapeutic strategy [5,[20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

The novel reversible LSD1 inhibitor SP-2577 promotes anti-tumor immunity in SWItch/Sucrose-NonFermentable (SWI/SNF) complex mutated ovarian cancer

et al. 2020

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Mutations of the SWI/SNF chromatin remodeling complex occur in 20% of all human cancers, including ovarian cancer. Approximately half of ovarian clear cell carcinomas (OCCC) carry mutations in the SWI/SNF subunit ARID1A, while small cell carcinoma of the ovary hypercalcemic type (SCCOHT) presents with inactivating mutations of the SWI/SNF ATPase SMARCA4 alongside epigenetic silencing of the ATPase SMARCA2. Loss of these ATPases disrupts SWI/SNF chromatin remodeling activity and may also interfere with the function of other histone-modifying enzymes that associate with or are dependent on SWI/ SNF activity. One such enzyme is lysine-specific histone demethylase 1 (LSD1/KDM1A), which regulates the chromatin landscape and gene expression by demethylating proteins such as histone H3. Cross-cancer analysis of the TCGA database shows that LSD1 is highly expressed in SWI/SNF-mutated tumors. SCCOHT and OCCC cell lines have shown sensitivity to the reversible LSD1 inhibitor SP-2577 (Seclidemstat), suggesting that SWI/SNFdeficient ovarian cancers are dependent on LSD1 activity. Moreover, it has been shown that inhibition of LSD1 stimulates interferon (IFN)-dependent anti-tumor immunity through induction of endogenous retroviral elements and may thereby overcome resistance to checkpoint blockade. In this study, we investigated the ability of SP-2577 to promote anti-tumor immunity and T-cell infiltration in SCCOHT and OCCC cell lines. We found that SP-2577 stimulated IFN-dependent anti-tumor immunity in SCCOHT and promoted the expression of PD-L1 in both SCCOHT and OCCC. Together, these findings suggest that the combination therapy of SP-2577 with checkpoint inhibitors may induce or augment immunogenic responses of SWI/SNF-mutated ovarian cancers and warrants further investigation.

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“…In contrast, OCCC targets women aged 55 years or older and is characterized by mutations in phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) (19,20) and phosphatase and tensin homolog (PTEN), in addition to the ARID1A mutations. Both SCCOHT and OCCC respond poorly to conventional chemotherapy, and to date there is no consensus on the optimal therapeutic strategy (5,(20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

The novel reversible LSD1 inhibitor SP-2577 promotes anti-tumor immunity in SWItch/Sucrose-NonFermentable (SWI/SNF) complex mutated ovarian cancer

Soldi

Halder

Weston

et al. 2020

Preprint

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Chromatin remodeling SWItch/Sucrose-NonFermentable (SWI/SNF) complexes, initially identified in yeast 20 years ago, are evolutionarily conserved multi-subunit protein complexes that use the energy from hydrolysis of adenosine triphosphate (ATP) to remodel nucleosome structure and modulate transcription. Mutations in proteins of SWI/SNF complexes occur in 20% of human cancers including ovarian cancer (OC). Approximately 50% of ovarian clear cell carcinoma (OCCC) carries mutations in the SWI/SNF subunit ARID1A while small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is driven primarily by genetic inactivation of the SWI/SNF ATPase SMARCA4 (BRG1) alongside epigenetic silencing of the homolog ATPase SMARCA2 (BRM). Dual loss of these ATPases disrupts SWI/SNF chromatin remodeling activity and may alsointerfere with the function of other histone-modifying enzymes that associate with or are dependent on SWI/SNF activity. One such enzyme is lysine-specific histone demethylase 1 (LSD1/KDM1A) which regulates the chromatin landscape and gene expression by demethylating proteins, including histone H3. LSD1 associates with epigenetic complexes such as the nucleosome remodeling deacetylase complex (NuRD) and SWI/SNF to inhibit the transcription of genes involved in tumor suppression and cell differentiation. TGCA analysis of human cancers shows that LSD1 is highly expressed in SWI/SNF-mutated tumors. Further, SCCOHT and OCCC cell lines show low nM IC 50 s for the reversible LSD1 inhibitor SP-2577 (Seclidemstat, currently in clinical phase I trials), supporting that these SWI/SNF-deficient ovarian cancers are dependent on LSD1 activity. Recently, it has been also shown that inhibition of LSD1 stimulates interferon (IFN)-dependent anti-tumor immunity through induction of Endogenous Retroviruses Elements (ERVs) and may thereby overcome resistance to checkpoint blockade. Additionally, SCCOHTs have been shown to exhibit an immune-active tumor microenvironment with PD-L1 expression in both tumor and stromal cells that strongly correlated with T cell infiltration. Thus, in this study we investigated the ability of SP-2577 to promote anti-tumor immunity and T cell infiltration in SWI/SNF-mutant SCCOHT and OCCC models. Our data shows that the reversible LSD1 inhibitor SP-2577 stimulates IFN-dependent anti-tumor immunity in SCCOHT cells in vitro in a 3D immuneorganoid platform. Additionally, SP-2577 promoted the expression of PD-L1 in both SCCOHT and OCCC models. Together our findings suggest that SP-2577 and checkpoint inhibitors as a therapeutic combination may induce or augment immunogenic responses in these tumors.

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Successful treatment of a stage IIIC small-cell carcinoma of the ovary hypercalcemic subtype using multi-modality therapeutic approach

Cited by 12 publications

References 22 publications

Primary ovarian small cell carcinoma of hypercalcemic type in a pregnant woman

Primary ovarian small cell carcinoma of hypercalcemic type in a pregnant woman

The novel reversible LSD1 inhibitor SP-2577 promotes anti-tumor immunity in SWItch/Sucrose-NonFermentable (SWI/SNF) complex mutated ovarian cancer

The novel reversible LSD1 inhibitor SP-2577 promotes anti-tumor immunity in SWItch/Sucrose-NonFermentable (SWI/SNF) complex mutated ovarian cancer

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